Copper Flashcards
What are the main copper containing enzymes?
Cytochrome C Oxidase - Respiratory chain (Copper acts a REDOX active substrate)
Dopamine B Hydroxylase - converts Dopamine to Norepinephrine (neurotransmitter)
Tyrosinase (rate limiting enzyme for melanin production - synthesises from the oxidation of tyrosine - found in melanosomes)
Sulfhyrdyl Oxidase - keratin cross linking
SOD - dismutation of superoxides
What other processes is copper crucial for?
Myelination (myelin sheath around nerves)
Circadium Rhythm (MYB TF)
Angiogensis (HIF 1 activation resulting in VEGF)
What are the 3 copper pathways in human cells?
Copper enters the cells via CTR1/2
Copper is then associated with specific chaperones:
Mitochondria (CCO) - chaperone unknown, however it is thought to be a small, soluble copper binding ligand which delivers Cu to COX1/2
SOD1 - CCS chaperone - 2 parts - 1 Zinc binding (structure) and 1 Copper binding (catalytic activity)
ATP7A/B - ATOX 1
Under high copper conditions, what happens to ATP7A/B
ATP7A translocates to the basolateral membrane of the enterocytes - increased export into blood
APT7B translocates to the apical membrane and releases copper into the bile
What is the TF involved in copper homeostasis?
SP1 - regulates CTR1 - decreased CTR1 increases activity of SP1 - increased transcription of CTR1 - increased copper uptake - contains a zinc finger domain (Zn - 2 cysteine/histadine) to sense Cu
What residues are key for CTR 1 internalisation?
Methionine
How can the body regulate for the NEED for copper, not the LEVELS?
In response to low O2, macrophages move to the site where there is low O2.
Increased CTR1 levels, increased Cu import to cells, increased Ceruloplasmin produced (an enzyme which can move iron around body) - results in increased production of haem and RBC
Also results in a decreased of CCS - not enough oxygen to cause ROS
How does systemic copper regulation work?
In response to low copper, there is a signal released from the heart (dont know what it is) that regulates ATP7A and B to increase copper in the blood
What is the structure of ATP7A/B
P Type ATPase - uses energy from ATP hydrolysis in order to move Cu across membranes
8 transmembrane domains (TMD) and 6 MBD (copper binding)
ATP domains:
N-domain (nucleotide binding domain) - ATP binding
P-domain (phosphorylation domain)
A-domain (Activation domain) - Phosphotase domain
How does ATPA7A/B move copper across the membrane?
Copper binds to each MBD (1-6) using ATOX-1 - this binding activates the process
CPC motif in TMD 6 binds Copper
ATP binds the N domain, and transfers a phosphate to the P domain - causes translocation of the Cu across the membrane
A domain dephosphorylates the P domain and the system returns to normal
What causes ATP7A/B to translocate from the TGN to the cell periphery?
COpper binding to MBD 5/6
How does copper homeostasis work in the Brain?
Increase in copper in the blood passes through the CTR 1 receptor on the apical membrane of the BBB - build up in the endothelial cells causes movement across basolateral membrane using ATP7A.
Copper taken up by CTR 1 into astrocytes, build up causes release by ATP7A
Copper taken up by Neurones via CTR1 - following depolarisation, Ca influx through NMDA receptor causes translocation of ATP7A from TGN to synaptic cleft
Release of Cu said to negatively regulate NMDA receptor - responsible for leaning/memory
How does copper affect the NMDA receptor?
Redox activity - modifies cysteine residues - prevents excitoxicity
What are the copper related diseases?
Menkes - low copper - ATP7A
Wilsons - High copper - ATP7B
Discuss Menkes disease
Build of copper in the small intestine and kidneys
Reduced copper in the blood (affect function of copper enzymes and NMDA regulation - over excitation)
Build up of copper in BBB and Brain-CSF barrier - reduced copper for neurones and glial cells
Classical MD/OHS
X linked recessive, 1 in 100,000
